2026年8月27日，美国加利福尼亚大学Kirsten Obernier等科学家在《科学》发表研究，通过系统绘制100个高置信度自闭症基因的蛋白质相互作用网络，揭示了致病突变如何驱动蛋白质网络的一致性重组及神经发育功能障碍。
蛋白质相互作用（PPI）网络的系统图谱绘制，以及确定自闭症谱系障碍（ASD）中致病突变如何重新布线这些网络，为揭示疾病机制和治疗机会提供了强大框架。研究人员利用亲和纯化-质谱技术，系统绘制了100个高置信度ASD基因的PPI图谱，发现了1800多种相互作用。通过评估致病错义突变的影响、利用AlphaFold，并在人源模型系统中验证关键发现，他们识别出野生型状态下共享蛋白复合物的显著趋同，以及由独立突变驱动的趋同性PPI重新布线。例如，FOXP1中不同的患者来源变异会破坏其与FOXP4的相互作用，导致脑类器官中皮层神经发生和神经活动的改变。总体而言，这些发现将遗传变异与蛋白质网络及ASD中趋同的神经发育功能障碍联系起来。
附：英文原文
Title: Autism mutations rewire protein interaction networks to drive neurodevelopmental pathology
Author: Belinda Wang, Rasika Vartak, Kelsey M. Hennick, Yefim Zaltsman, Zun Zar Chi Naing, Benjamin J. Polacco, Ali Bashir, Manon Eckhardt, Mehdi Bouhaddou, Jiewei Xu, Nawei Sun, Micaela C. Lasser, Yuan Zhou, Justin McKetney, Keelan Z. Guiley, Pawel Gniewek, Una Chan, Naufa Amirani, Owen Griffiths, Nishant Chadha, Reshmi Tognatta, Merve Cakir, Martin Gordon, Prachi Khare, Sam Drake, Vanessa Drury, David F. Burke, Silvano Gonzalez, Sahar Alkhairy, Reuben Thomas, Stephanie Lam, Montana Morris, Ethel Bader, Mélanie Dos Santos, Anastassia V. Komarova, Maxwell Bennett, Craig Ennis, Octavio Castillo, Yvonne Lim, Robert Martin, Meghan Seyler, Tierney Baum, Rebecca Krasnoff, George Wang, Sagnik Middya, Sheng Wang, Presley Pham, Juan Arbelaez, Dexter Pratt, Sofia Bali, Shivali Chag, Julia A. Kaye, Nadir Mahmood, Lee Spraggon, Thomas Rolland, Shawn Hervey-Jumper, James S. Fraser, Thomas Bourgeron, Steven Finkbeiner, Caroline Demeret, Danielle L. Swaney, Sourav Bandyopadhyay, Trey Ideker, Pedro Beltrao, Helen Rankin Willsey, Ruth Hüttenhain, Kirsten Obernier, Tomasz J. Nowakowski, Matthew W. State, A. Jeremy Willsey, Nevan J. Krogan
Issue&Volume: 2026-08-27
Abstract: Systematic mapping of protein-protein interaction (PPI) networks and determining how causal mutations rewire them in autism spectrum disorder (ASD) provide a powerful framework for uncovering disease mechanisms and therapeutic opportunities. Using affinity purification–mass spectrometry, we systematically mapped PPIs for 100 high-confidence ASD genes, uncovering more than 1800 interactions. By assessing the impact of pathogenic missense mutations, leveraging AlphaFold, and validating key findings in human-derived model systems, we identified marked convergence onto shared protein complexes in the wild-type state and convergent PPI rewiring driven by independent mutations. For example, distinct patient-derived variants in FOXP1 disrupt its interactions with FOXP4, leading to changes in cortical neurogenesis and neural activity in brain organoids. Overall, these findings link genetic variation to protein networks and convergent neurodevelopmental dysfunction in ASD.
DOI: 10.1126/science.ady4523
Source: https://www.science.org/doi/10.1126/science.ady4523